Hypertension (HTN) is the most common chronic disease in the United States, and is a leading cause of stroke, acute myocardial infarction (MI), heart failure and kidney failure. There are numerous effective antihypertensive drug classes, but only about half of patients have a good response to any given drug. Pharmacogenetics might significantly improve BP control and outcomes, as genetically-guided drug therapy selection could dramatically increase the number of patients who receive the best drug for their HTN. We propose to test pharmacogenetic hypotheses that center on BP response and outcomes (death, MI, stroke) in HTN, using 5,871 genomic DNA samples we have collected from participants in INVEST, a large, international trial in patients with HTN and ischemic heart disease. We propose to test the following hypotheses: Hypothesis 1: Genetic variability in the proteins important to verapamil's pharmacologic action contribute to interpatient variability in verapamil's antihypertensive effect. Specific Aim 1A. Identify sequence variability in the genes for the major L-type Ca channel (LTCC) subunits alpha1C and beta, the sarcoplasmlc retlculum Ca2+-ATPase 2, the Ca2+-activated K channel, and critical portions of the ryanodine receptor by resequencing the genes in Corriel DNA from 60 individuals. Predict those polymorphisms most likely to be functionally significant using various bioinformatics techniques. Specific Aim lB. Perform in vitro functional studies, including ion channel patch-clamp studies, to test for functional significance of polymorphisms in the LTCC a1C subunit. Specific Aim 1C. Determine the association between verapamil's antihypertensive effect and genetic polymorphisms of interest, as identified in Aim 1A. Hypothesis 2: Antihypertensives that target the underlying molecular/genetic basis of a patient's HTN will result in better outcomes than antihypertensives that do not target the underlying pathophysiology. Specific Aim 2. Determine whether drug therapy that is targeted at a "drug response" polymorphism or haplotype results in better patient outcomes (specifically fewer deaths, strokes, MIs) than therapy that does not target the "drug response" polymorphism(s). This hypothesis will be tested for all four study drugs: atenolol, verapamil, hydrochlorothiazide and trandolapril. Because of the diversity of the INVEST genetics sample (47% Hispanic (mostly Puerto Ricans), 38% Caucasian and 11% African American), we will test Hypothesis 3: Use of molecular markers to define genetic heterogeneity in the study population is superior to race/ethnicity information in genetic associations with drug response. Specific Aim 3A. Determine whether models of genetic association with drug response perform better with use of genetic marker-defined population cluster and individual ancestral proportion information than with clinician-defined information on race/ethnicity. Specific Aim 3B. Document that any positive associations between drug response and genotype are not the result of population stratification or admixture. These aims will be accomplished by genotyping patients for at least 50 Ancestral Informative Markers. The proposed studies will provide considerable new evidence regarding the pharmacogenetics of verapamil, and will significantly further our understanding of the pharmacogenetics of p-blockers, thiazide diuretics, and ACE inhibitors. They will substantially enhance our understanding of the genetic variability in proteins important to Ca ++ regulation and response to CCBs and other drugs, and the functional significance of this genetic variability. Finally, the proposed studies will increase our understanding of the role of molecular markers for defining population stratification and admixture in pharmacogenetic studies. The proposed studies should add substantial new information about antihypertensive pharmacogenetics, and could influence how antihypertensive medications are prescribed in the future.